Compositions and methods of expansion of T cell populations

Abstract

The present disclosure generally relates to compositions and methods useful for an adoptive cell therapy. Some embodiments of the disclosure relates to methods for producing a population of lymphocytes enriched in T stem cell memory cells (T SCM cells). Further provided are compositions containing a substantially pure population of T SCM cells that are therapeutically effective in treating various cancers, and kits containing such compositions. Methods for treating a subject having or suspected of having a cancer using the compositions and kits as disclosed herein are also provided.

What is claimed is: 
     
       1. A method of producing a population of lymphocytes enriched in T stem cell memory cells (T SCM  cells), the method comprising contacting a sample comprising naturally occurring T cells or engineered T cells with an agent comprising PCI-32765 (ibrutinib),
 wherein the sample is in contact with the agent during Day 0-3 of the culturing in an amount sufficient to produce a population of lymphocytes enriched in T SCM  cells. 
 
     
     
       2. The method of  claim 1 , wherein the sample is a biological sample isolated from a subject. 
     
     
       3. The method of  claim 2 , wherein the biological sample comprises one or more of the following: tumor-infiltrating lymphocytes (TILs), peripheral blood mononuclear cells (PBMCs), human naïve T cells, human primary T cells. 
     
     
       4. The method of  claim 1 , wherein the sample comprises engineered T cells expressing chimeric antigen receptors (CARs) and/or T cell receptors (TCRs). 
     
     
       5. The method of  claim 1 , wherein the percentage of T SCM  cells in the total cells is increased by about 0.5-fold to about 200-fold after said contacting with the agent when compared to the percentage of T SCM  cells in the total cells prior to said contacting. 
     
     
       6. The method of  claim 1 , wherein the percentage of non-T SCM  cells in the total cells is decreased by about 0.5-fold to about 200-fold after said contacting with the agent when compared to the percentage of non-T SCM  cells in the total cells prior to said contacting. 
     
     
       7. The method of  claim 1 , wherein the agent decreases the activity of the Bruton's tyrosine kinase (BTK) signaling pathway and/or the activity of the inducible T cell kinase (ITK) signaling pathway. 
     
     
       8. The method of  claim 2 , wherein the subject has cancer. 
     
     
       9. The method of  claim 8 , where said cancer is selected from the group consisting of chronic lymphocytic leukemia (CLL), acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic myeloid leukemia (CMIL), lymphomas, brain cancers, blood cancers and melanomas. 
     
     
       10. The method of  claim 1 , wherein the T SCM  cells express one or more of the following: CD7, CD11a, CD27, CD45RA, CD58, CD95, CD127 and CCR7; and/or wherein the T SCM  cells do not express one or more of the following: CD45RO, CD57, LAG3, CTLA4 and PD1. 
     
     
       11. The method of  claim 1 , wherein the T SCM  cells produce more effector cytokines IFN-γ and TNF-α as compared to control effector cells. 
     
     
       12. The method of  claim 1 , wherein the sample is contacted with the agent prior to expansion of the T cells. 
     
     
       13. The method of  claim 1 , wherein the sample is contacted with the agent less than about 24 hours after T cell expansion initiation. 
     
     
       14. The method of  claim 1 , further comprising culturing the sample and agent in a culture medium for about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 days. 
     
     
       15. The method of  claim 13 , wherein the sample is in contact with the agent only during days 0-2 or days 0-3 of the culturing. 
     
     
       16. The method of  claim 13 , wherein the agent is present during days 0-2 or days 0-3 of the culturing at a concentration sufficient to produce a population of lymphocytes enriched in T SCM  cells, followed by a decrease of the agent concentration in the culture. 
     
     
       17. The method of  claim 14 , wherein the agent comprises ibrutinib and is present at a concentration of about 1.6 μM during days 0-2, and at a concentration of about 0.32 μM during days 3-10 of the culturing. 
     
     
       18. The method of  claim 14 , wherein the agent comprises ibrutinib and is present at a concentration of about 1.6 μM during days 0-2, about 0.32 μM during days 3-6, and about 0 μM during days 7-10 of the culturing. 
     
     
       19. The method of  claim 1 , wherein the T SCM  cells produce more of the proliferation-inducing cytokine IL-2 and less effector cytokines IFN-7 and TNF-α as compared to control effector cells.